Background
Methods
Study population
Data collection and outcome variables
Characteristic | Non-obese group (BMI < 30.0) | Obese group (BMI ≥ 30.0) | ||
---|---|---|---|---|
(n = 3675) | (n = 1704) | |||
n | (%) | n | (%) | |
Age in years, median (range) | 68 | (50–79) | 67 | (50–71)* |
Education | ||||
≤ High school | 1272 | (34.6) | 701 | (41.1)* |
> High school | 2403 | (65.4) | 1003 | (58.9) |
Family history of diabetes mellitus | ||||
No | 2714 | (73.9) | 1122 | (65.8)* |
Yes | 961 | (26.1) | 582 | (34.2) |
Family history of cancer | ||||
No | 1327 | (36.1) | 567 | (33.3) |
Yes | 2348 | (63.9) | 1137 | (66.7) |
Family history of breast cancer | ||||
No | 3070 | (83.5) | 1428 | (83.8) |
Yes | 605 | (16.5) | 276 | (16.2) |
Family history of colorectal cancer | ||||
No | 3106 | (84.5) | 1430 | (83.9) |
Yes | 569 | (15.5) | 274 | (16.1) |
Cardiovascular disease ever | ||||
No | 3161 | (86.0) | 1430 | (83.9) |
Yes | 514 | (14.0) | 274 | (16.1) |
Hypertension ever | ||||
No | 2702 | (73.5) | 1026 | (60.2)* |
Yes | 973 | (26.5) | 678 | (39.8) |
High cholesterol requiring pills ever | ||||
No | 3178 | (86.5) | 1460 | (85.7) |
Yes | 497 | (13.5) | 244 | (14.3) |
Smoking status | ||||
Never | 1882 | (51.2) | 897 | (52.6)* |
Past | 1498 | (40.8) | 705 | (41.4) |
Current | 295 | (8.0) | 102 | (6.0) |
Lifetime partner | ||||
Have never had sex | 56 | (1.5) | 38 | (2.2) |
Have had sex | 3619 | (98.5) | 1666 | (97.8) |
Depressive symptoma
| ||||
< 0.06 | 3392 | (92.3) | 1556 | (91.3) |
≥ 0.06 | 283 | (7.7) | 148 | (8.7) |
METs·hour·week-1 b
| ||||
< 10 | 1875 | (51.0) | 1160 | (68.1)* |
≥ 10 | 1800 | (49.0) | 544 | (31.9) |
Total HEI-2005 score, median (range)c
| 68.7 | (25.8–90.8) | 65.7 | (27.9–91.2)* |
Dietary total sugars in g, median (range) | 91.6 | (4.6–350.2) | 94.9 | (10.8–474.5)* |
Dietary alcohol per day in g, median (range) | 1.506 | (0.0–106.7) | 0.561 | (0.0–148.6)* |
% calories from fatd
| ||||
< 40% | 3057 | (83.2) | 1268 | (74.4)* |
≥ 40% | 618 | (16.8) | 436 | (25.6) |
Waist circumference in cm, median (range) | 81.0 | (37.5–177.0) | 100.0 | (69.0–191.8)* |
Waist-to-hip ratio, median (range) | 0.798 | (0.341–1.893) | 0.849 | (0.633–1.696)* |
Oral contraceptive use | ||||
Never | 2448 | (66.6) | 1123 | (65.9) |
Ever | 1227 | (33.4) | 581 | (34.1) |
History of hysterectomy or oophorectomy | ||||
No | 2457 | (66.9) | 1006 | (59.0)* |
Yes | 1218 | (33.1) | 698 | (41.0) |
Age at menarche in years, median (range) | 13 | (≤ 9–≥ 17) | 12 | (≤ 9–≥ 17)* |
Age at menopause in years, median (range) | 50 | (20–60) | 50 | (21–60) |
Pregnancy history | ||||
No | 276 | (7.5) | 134 | (7.9) |
Yes | 3399 | (92.5) | 1570 | (92.1) |
Breastfeeding at least one month | ||||
No | 1649 | (44.9) | 812 | (47.7) |
Yes | 2026 | (55.1) | 892 | (52.3) |
Exogenous estrogen use | ||||
No | 2224 | (60.5) | 1122 | (65.8)* |
Yes | 1451 | (39.5) | 582 | (34.2) |
Glucose in mg/dl, median (range) | 92.0 | (39.0–369.0) | 97.0 | (62.0–347.0)* |
Insulin in μIU/ml, median (range) | 5.5 | (0.5–119.4) | 9.8 | (0.3–57.0)* |
HOMA-IR, median (range) | 1.3 | (0.1–25.1) | 2.4 | (0.1–42.3)* |
Genotyping and laboratory methods
Statistical analysis
Results
Breast cancer risk associated with glucose metabolism-related SNPs mediated through glucose metabolism traits, stratified by obesity status (BMI, waist, and w/h), level of physical activity, and dietary fat intake
SNP | Nearest gene | Effect allele/Other allele | Favorable Energy Balance Group | Unfavorable Energy Balance Group | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Direct effect | Indirect effect | Total effect | Direct effect | Indirect effect | Total effect | |||||||||
Breast cancer risk in relation to SNP through pathways other than glucose
| Breast cancer risk in relation to SNP through glucose
| Breast cancer risk in relation to SNP | Breast cancer risk in relation to SNP through pathways other than glucose
| Breast cancer risk in relation to SNP through glucose
| Breast cancer risk in relation to SNP | |||||||||
HRa
| 95% CI | Effect sizea
| 95% CI | HRa
| 95% CI | HRa
| 95% CI | Effect sizea
| 95% CI | HRa
| 95% CI | |||
BMIb
| ||||||||||||||
rs560887 |
G6PC2
| T/C | 1.11 | (0.89–1.39) | 0.01 | (−0.04–0.02) | 1.12 | (0.90–1.39) |
1.34
|
(1.04–1.73)
| −0.004 | (−0.01–0.02) |
1.35
|
(1.05–1.74)
|
Waistc
| ||||||||||||||
rs560887 |
G6PC2
| T/C | 1.09 | (0.85–1.39) | 0.004 | (−0.02–0.01) | 1.10 | (0.86–1.40) |
1.35
|
(1.07–1.70)
| −0.01 | (−0.01–0.02) |
1.33
|
(1.06–1.66)
|
w/h Ratiod
| ||||||||||||||
rs560887 |
G6PC2
| T/C | 1.07 | (0.89–1.39) | 0.01 | (−0.03–0.01) | 1.10 | (0.89–1.36) |
1.47
|
(1.13–1.92)
| −0.003 | (−0.003–0.01) |
1.42
|
(1.10–1.85)
|
rs780094 |
GCKR
| C/T | 1.01 | (0.82–1.23) | −0.01 | (−0.03–0.01) | 1.02 | (0.84–1.24) |
1.33
|
(1.00–1.76)
| 0.002 | (−0.003–0.01) | 1.22 | (0.93–1.60) |
rs35767 |
IGF1
| A/G | 0.91 | (0.68–1.21) | 0.002 | (−0.01–0.004) | 0.93 | (0.70–1.23) |
1.43
|
(1.03–1.98)
| <0.001 | (−0.004–0.004) |
1.48
|
(1.08–2.03)
|
Dietary fat intakee
| ||||||||||||||
rs560887 |
G6PC2
| T/C | 1.14 | (0.95–1.37) | −0.01 | (−0.003–0.02) | 1.14 | (0.95–1.37) |
1.56
|
(1.07–2.28)
| 0.02 | (−0.07–0.03) |
1.59
|
(1.10–2.31)
|
SNP | Nearest gene | Effect allele/Other allele | Favorable Energy Balance Group | Unfavorable Energy Balance Group | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Direct effect | Indirect effect | Total effect | Direct effect | Indirect effect | Total effect | |||||||||
Breast cancer risk in relation to SNP through pathways other than HOMA-IR
| Breast cancer risk in relation to SNP through HOMA-IR
| Breast cancer risk in relation to SNP | Breast cancer risk in relation to SNP through pathways other than HOMA-IR
| Breast cancer risk in relation to SNP through HOMA-IR
| Breast cancer risk in relation to SNP | |||||||||
HRa
| 95% CI | Effect sizea
| 95% CI | HRa
| 95% CI | HRa
| 95% CI | Effect sizea
| 95% CI | HRa
| 95% CI | |||
BMIb
| ||||||||||||||
rs560887 |
G6PC2
| T/C | 1.17 | (0.93–1.46) | <0.001 | (−0.003–0.003) | 1.12 | (0.90–1.39) |
1.35
|
(1.04–1.76)
| <0.001 | (−0.02–0.02) |
1.35
|
(1.05–1.74)
|
Waistc
| ||||||||||||||
rs560887 |
G6PC2
| T/C | 1.11 | (0.86–1.42) | −0.003 | (−0.01–0.01) | 1.10 | (0.86–1.40) |
1.39
|
(1.10–1.77)
| −0.002 | (−0.01–0.01) |
1.33
|
(1.06–1.66)
|
Waist/hip Ratiod
| ||||||||||||||
rs560887 |
G6PC2
| T/C | 1.11 | (0.72–1.12) | 0.001 | (−0.01–0.004) | 1.10 | (0.89–1.36) |
1.50
|
(1.14–1.97)
| −0.001 | (−0.01–0.01) |
1.42
|
(1.10–1.85)
|
rs35767 |
IGF1
| A/G | 0.92 | (0.69–1.24) | 0.001 | (−0.01–0.003) | 0.93 | (0.70–1.23) |
1.42
|
(1.02–1.98)
| −0.002 | (−0.01–0.01) |
1.48
|
(1.08–2.03)
|
Dietary fat intakee
| ||||||||||||||
rs560887 |
G6PC2
| T/C | 1.16 | (0.96–1.41) | 0.01 | (−0.01–0.003) | 1.14 | (0.95–1.37) |
1.59
|
(1.08–2.34)
| 0.003 | (−0.02–0.02) |
1.59
|
(1.10–2.31)
|
CRC risk associated with glucose metabolism-related SNPs mediated through glucose metabolism traits, stratified by obesity status (BMI, waist, and w/h), level of physical activity, and dietary fat intake
SNP | Nearest gene | Favorable Energy Balance Group | Unfavorable Energy Balance Group | |||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Direct effect | Indirect effect | Total effect | Direct effect | Indirect effect | Total effect | |||||||||
Effect allele/Other allele | CRC risk in relation to SNP through pathways other than glucose
| CRC risk in relation to SNP through glucose
| CRC risk in relation to SNP | CRC risk in relation to SNP through pathways other than glucose
| CRC risk in relation to SNP through glucose
| CRC risk in relation to SNP | ||||||||
HRa
| 95% CI | Effect sizea
| 95% CI | HRa
| 95% CI | HRa
| 95% CI | Effect sizea
| 95% CI | HRa
| 95% CI | |||
BMIb
| ||||||||||||||
rs4607517 |
GCK
| G/A | 0.79 | (0.60–1.02) |
0.02
|
(0.002–0.04)
|
0.80
|
(0.64–1.00)
| 1.00 | (0.65–1.55) | 0.001 | (−0.01–0.01) | 1.06 | (0.75–1.51) |
rs174550 |
FADS1
| T/C | 1.15 | (0.92–1.43) | −0.002 | (−0.01–0.01) | 1.05 | (0.87–1.27) | 1.40 | (0.97–2.03) | <0.001 | (−0.01–0.01) |
1.37
|
(1.02–1.83)
|
rs11605924 |
CRY2
| C/A | 0.89 | (0.73–1.09) | −0.004 | (−0.01–0.02) |
0.82
|
(0.69–0.98)
| 1.32 | (0.94–1.85) | <0.001 | (−0.004–0.004) | 1.07 | (0.82–1.39) |
Waistc
| ||||||||||||||
rs560887 |
G6PC2
| T/C |
0.75
|
(0.58–0.99)
| 0.01 | (−0.03–0.004) | 0.88 | (0.70–1.11) | 1.00 | (0.75–1.34) | 0.01 | (−0.04–0.02) | 1.01 | (0.80–1.27) |
rs174550 |
FADS1
| T/C | 1.17 | (0.91–1.51) | −0.01 | (−0.02–0.01) | 1.03 | (0.83–1.28) | 1.23 | (0.93–1.63) | 0.01 | (−0.01–0.02) |
1.25
|
(1.00–1.57)
|
rs11605924 |
CRY2
| C/A | 0.84 | (0.67–1.06) | −0.01 | (−0.01–0.02) |
0.81
|
(0.66–0.99)
| 1.20 | (0.92–1.56) | 0.004 | (−0.02–0.01) | 0.97 | (0.79–1.20) |
w/h Ratiod
| ||||||||||||||
rs10885122 |
ADRA2A
| G/T | 0.80 | (0.59–1.07) | −0.002 | (−0.01–0.01) | 0.84 | (0.64–1.08) | 1.36 | (0.81–2.30) | <0.001 | (−0.003–0.003) |
1.58
|
(1.01–2.48)
|
Physical activity levele
| ||||||||||||||
rs4607517 |
GCK
| G/A | 0.73 | (0.52–1.00) | 0.01 | (−0.01–0.04) |
0.72
|
(0.55–0.95)
| 0.95 | (0.70–1.31) | 0.01 | (−0.01–0.02) | 0.99 | (0.76–1.28) |
Dietary fat intakef
| ||||||||||||||
rs4607517 |
GCK
| G/A | 0.91 | (0.71–1.17) | 0.01 | (−0.004–0.03) | 0.94 | (0.76–1.17) | 0.57 | (0.33–1.01) | −0.003 | (−0.01–0.01) |
0.66
|
(0.43–1.00)
|
rs11558471 |
SLC30A8
| A/G | 1.07 | (0.87–1.31) | −0.02 | (−0.04–0.004) | 0.95 | (0.80–1.12) | 1.60 | (0.93–2.75) | −0.002 | (−0.01–0.01) |
1.60
|
(1.07–2.40)
|
SNP | Nearest gene | Effect allele/ Other allele | Favorable Energy Balance Group | Unfavorable Energy Balance Group | ||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Direct effect | Indirect effect | Total effect | Direct effect | Indirect effect | Total effect | |||||||||
CRC risk in relation to SNP through pathways other than HOMA-IR
| CRC risk in relation to SNP through HOMA-IR
| CRC risk in relation to SNP | CRC risk in relation to SNP through pathways other than HOMA-IR
| CRC risk in relation to SNP through HOMA-IR
| CRC risk in relation to SNP | |||||||||
HRa
| 95% CI | Effect sizea
| 95% CI | HRa
| 95% CI | HRa
| 95% CI | Effect sizea
| 95% CI | HRa
| 95% CI | |||
BMIb
| ||||||||||||||
rs2191349 | DGKB/TMEM195 | G/T | 1.04 | (0.84–1.28) | <0.001 | (−0.004–0.004) | 1.07 | (0.90–1.28) |
1.45
|
(1.03–2.03)
| <0.001 | (−0.003–0.003) | 1.17 | (0.90–1.52) |
rs4607517 |
GCK
| G/A | 0.79 | (0.61–1.03) | <0.001 | (−0.01–0.01) |
0.80
|
(0.64–1.00)
| 1.04 | (0.66–1.62) | <0.001 | (−0.004–0.003) | 1.06 | (0.75–1.51) |
rs174550 |
FADS1
| T/C | 1.16 | (0.93–1.45) | <0.001 | (−0.001–0.001) | 1.05 | (0.87–1.27) | 1.40 | (0.96–2.04) | −0.01 | (−0.02–0.01) |
1.37
|
(1.02–1.83)
|
rs11605924 |
CRY2
| C/A | 0.87 | (0.71–1.07) | <0.001 | (−0.01–0.01) |
0.82
|
(0.69–0.98)
| 1.32 | (0.93–1.87) | <0.001 | (−0.003–0.003) | 1.07 | (0.82–1.39) |
Waistc
| ||||||||||||||
rs2191349 | DGKB/TMEM195 | G/T | 0.97 | (0.76–1.23) | 0.002 | (−0.01–0.01) | 1.00 | (0.81–1.23) |
1.37
|
(1.05–1.79)
| −0.002 | (−0.004–0.01) | 1.20 | (0.97–1.48) |
rs174550 |
FADS1
| T/C | 1.22 | (0.94–1.58) | −0.002 | (−0.01–0.01) | 1.03 | (0.83–1.28) | 1.24 | (0.93–1.65) | −0.01 | (−0.02–0.002) |
1.25
|
(1.00–1.57)
|
rs11605924 |
CRY2
| C/A | 0.84 | (0.67–1.06) | <0.001 | (−0.01–0.01) |
0.81
|
(0.66–0.99)
| 1.17 | (0.90–1.54) | <0.001 | (−0.01–0.01) | 0.97 | (0.79–1.20) |
Waist/hip Ratiod
| ||||||||||||||
rs2191349 | DGKB/TMEM195 | G/T | 1.04 | (0.84–1.29) | 0.003 | (−0.01–0.004) | 1.03 | (0.86–1.23) |
1.38
|
(1.00–1.89)
| <0.001 | (−0.01–0.01) | 1.24 | (0.97–1.59) |
rs10885122 |
ADRA2A
| G/T | 0.78 | (0.58–1.05) | <0.001 | (−0.01–0.01) | 0.84 | (0.64–1.08) | 1.31 | (0.77–2.20) | <0.001 | (−0.01–0.01) |
1.58
|
(1.01–2.48)
|
rs174550 |
FADS1
| T/C | 1.15 | (0.92–1.45) | 0.002 | (−0.004–0.01) | 1.08 | (0.89–1.30) |
1.43
|
(1.01–2.03)
| −0.008 | (−0.02–0.004) | 1.27 | (0.97–1.66) |
Physical activity levele
| ||||||||||||||
rs4607517 |
GCK
| G/A | 0.73 | (0.52–1.01) | <0.001 | (−0.003–0.003) |
0.72
|
(0.55–0.95)
| 0.95 | (0.69–1.31) | −0.001 | (−0.01–0.004) | 0.99 | (0.76–1.28) |
Dietary fat intakef
| ||||||||||||||
rs4607517 |
GCK
| G/A | 0.92 | (0.72–1.18) | <0.001 | (−0.01–0.004) | 0.94 | (0.76–1.17) | 0.58 | (0.33–1.03) | −0.001 | (−0.01–0.001) |
0.66
|
(0.43–1.00)
|
rs11558471 |
SLC30A8
| A/G | 1.08 | (0.88–1.33) | <0.001 | (−0.01–0.01) | 0.95 | (0.80–1.12) | 1.64 | (0.94–2.85) | −0.003 | (−0.01–0.01) |
1.60
|
(1.07–2.40)
|